肝衰竭与肠道屏障损害关系的研究进展

肖玲燕; 邢阿雯; 谭善忠

doi:10.3969/j.issn.1001-5256.2021.11.049

肝衰竭与肠道屏障损害关系的研究进展

DOI: 10.3969/j.issn.1001-5256.2021.11.049

1a.
南京中医药大学附属南京医院重症医学科，南京 210003
1b.
南京中医药大学附属南京医院中西医结合肝病，南京 210003
2.
南京中医药大学医学院·整合医学院，南京 210023

基金项目:

江苏省中医药领军人才项目 (SLJ0216)

详细信息

通信作者:
谭善忠，doctor_tsz@aliyun.com

中图分类号: R575.3
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- 文章访问数: 435
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- 被引次数: 0
出版历程
- 收稿日期: 2021-04-08
- 录用日期: 2021-07-01
- 出版日期: 2021-11-20

Research advances in the association between liver failure and intestinal barrier injury

1a.
Department of Critical Care Medicine, Nanjing Hospital Affiliated to Nanjing University of Chinese Medicine, Nanjing 210003, China
1b.
Department of Integrated Traditional Chinese and Western Medicine for Liver Diseases, Nanjing Hospital Affiliated to Nanjing University of Chinese Medicine, Nanjing 210003, China
2.
School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China

Research funding:

the Leading Talent Project of Jiangsu Province Traditional Chinese Medicine (SLJ0216)

摘要

摘要: 肝衰竭与肠道屏障损害尤其是肠道微生态失衡相互影响，互为因果。肝衰竭时肠道屏障包括化学物质、机械、免疫和微生物屏障发生损害，同时由于肠道微生态失调、细菌内毒素增加及胆汁酸代谢异常等影响肝细胞再生，增加并发症的产生，可加重肝衰竭病情。治疗肝衰竭应同时重视肠道屏障功能的维护，针对肠道屏障损害尤其是微生态紊乱的治疗是比较有前景的治疗方法。
- 肝功能衰竭 /
- 肠黏膜屏障 /
- 胃肠道微生物组 /
- 治疗学
Abstract: Liver failure and intestinal barrier injury, especially intestinal microflora imbalance, interacts as both the cause and effect of each other. Intestinal barrier injury is observed during liver failure, including the injuries of chemical, mechanical, immune, and microbial barriers, and meanwhile, gut dysbiosis, increased bacterial endotoxins, and abnormal bile acid metabolism may affect hepatocyte regeneration, increase complications, and aggravate the conditions of liver failure. The maintenance of intestinal barrier function should be taken seriously in the treatment of liver failure, and the treatment targeting intestinal barrier injury, especially microecological disturbance, is a promising method.
- Liver Failure /
- Intestinal Mucosal Barrier /
- Gastrointestinal Microbiome /
- Therapeutics

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参考文献(51)

[1]	BERNAL W, WENDON J. Acute liver failure[J]. N Engl J Med, 2013, 369(26): 2525-2534. DOI: 10.1056/NEJMra1208937.
[2]	ARROYO V, MOREAU R, JALAN R. Acute-on-chronic liver failure[J]. N Engl J Med, 2020, 382(22): 2137-2145. DOI: 10.1056/NEJMra1914900.
[3]	WILMORE DW, SMITH RJ, O'DWYER ST, et al. The gut: A central organ after surgical stress[J]. Surgery, 1988, 104(5): 917-923.
[4]	MARSHALL JC. The gut as a potential trigger of exercise-induced inflammatory responses[J]. Can J Physiol Pharmacol, 1998, 76(5): 479-484. DOI: 10.1139/cjpp-76-5-479.
[5]	VAISHNAVA S, YAMAMOTO M, SEVERSON KM, et al. The antibacterial lectin RegⅢgamma promotes the spatial segregation of microbiota and host in the intestine[J]. Science, 2011, 334(6053): 255-258. DOI: 10.1126/science.1209791.
[6]	CHEN S, LI X, LI M, et al. Mucosal expression of defensin-5, soluble phospholipase A2 and lysozyme in the intestine in a rat model of acute liver failure and its relationship to intestinal bacterial translocation[J]. Gastroenterol Hepatol, 2020, 43(6): 293-300. DOI: 10.1016/j.gastrohep.2020.01.004.
[7]	KRAUSE G, WINKLER L, MUELLER SL, et al. Structure and function of claudins[J]. Biochim Biophys Acta, 2008, 1778(3): 631-645. DOI: 10.1016/j.bbamem.2007.10.018.
[8]	XIANG T, GE S, WEN J, et al. The possible association between AQP9 in the intestinal epithelium and acute liver injury-induced intestinal epithelium damage[J]. Mol Med Rep, 2018, 18(6): 4987-4993. DOI: 10.3892/mmr.2018.9542.
[9]	WANG Y, CHEN H, CHEN Q, et al. The protective mechanism of CAY10683 on intestinal mucosal barrier in acute liver failure through LPS/TLR4/MyD88 pathway[J]. Mediators Inflamm, 2018, 2018: 7859601. DOI: 10.1155/2018/7859601.
[10]	CHEN Q, WANG Y, JIAO F, et al. Betaine inhibits Toll-like receptor 4 responses and restores intestinal microbiota in acute liver failure mice[J]. Sci Rep, 2020, 10(1): 21850. DOI: 10.1038/s41598-020-78935-6.
[11]	WIEST R, LAWSON M, GEUKING M. Pathological bacterial translocation in liver cirrhosis[J]. J Hepatol, 2014, 60(1): 197-209. DOI: 10.1016/j.jhep.2013.07.044.
[12]	FU J, LI G, WU J, et al. Intestinal IgA positive lymphocytes in acute liver necrosis decrease due to lymphocyte homing disturbance and apoptosis[J]. Rev Esp Enferm Dig, 2019, 111(2): 101-105. DOI: 10.17235/reed.2018.5656/2018.
[13]	ENGELMANN C, SHEIKH M, SHARMA S, et al. Toll-like receptor 4 is a therapeutic target for prevention and treatment of liver failure[J]. J Hepatol, 2020, 73(1): 102-112. DOI: 10.1016/j.jhep.2020.01.011.
[14]	WANG YH, GAO Y. Research progress in diagnosis and treatment of non-alcoholic fatty liver disease combinated with type 2 diabetes mellitus[J]. J Jilin Univ(Med Edit), 2020, 46(6): 1324-1331. DOI: 10.13481/j.1671-587x.20200634. 王雨涵, 高影. 非酒精性脂肪性肝病并发2型糖尿病诊断和治疗的研究进展[J]. 吉林大学学报(医学版), 2020, 46(6): 1324-1331. DOI: 10.13481/j.1671-587x.20200634.
[15]	BELLOT P, FRANCÉS R, SUCH J. Pathological bacterial translocation in cirrhosis: Pathophysiology, diagnosis and clinical implications[J]. Liver Int, 2013, 33(1): 31-39. DOI: 10.1111/liv.12021.
[16]	CHOPYK DM, GRAKOUI A. Contribution of the intestinal microbiome and gut barrier to hepatic disorders[J]. Gastroenterology, 2020, 159(3): 849-863. DOI: 10.1053/j.gastro.2020.04.077.
[17]	YANG R, ZOU X, TENHUNEN J, et al. HMGB1 neutralization is associated with bacterial translocation during acetaminophen hepatotoxicity[J]. BMC Gastroenterol, 2014, 14: 66. DOI: 10.1186/1471-230X-14-66.
[18]	HU YX, YU L, LIU HJ, et al. Changes in the composition of intestinal microbiota in mice with acute liver failure induced by D-galactosamine[J]. Chin J Hepatol, 2017, 25(4): 291-296. DOI: 10.3760/cma.j.issn.1007-3418.2017.04.011. 胡亚欣, 余蕾, 刘华娟, 等. 急性肝衰竭小鼠肠道微生态的变化[J]. 中华肝脏病杂志, 2017, 25(4): 291-296. DOI: 10.3760/cma.j.issn.1007-3418.2017.04.011.
[19]	CHEN Y, GUO J, QIAN G, et al. Gut dysbiosis in acute-on-chronic liver failure and its predictive value for mortality[J]. J Gastroenterol Hepatol, 2015, 30(9): 1429-1437. DOI: 10.1111/jgh.12932.
[20]	MACPHERSON AJ, HEIKENWALDER M, GANAL-VONARBURG SC. The liver at the nexus of host-microbial interactions[J]. Cell Host Microbe, 2016, 20(5): 561-571. DOI: 10.1016/j.chom.2016.10.016.
[21]	HARTMANN N, KRONENBERG M. Cancer immunity thwarted by the microbiome[J]. Science, 2018, 360(6391): 858-859. DOI: 10.1126/science.aat8289.
[22]	ARROYO V, MOREAU R, KAMATH PS, et al. Acute-on-chronic liver failure in cirrhosis[J]. Nat Rev Dis Primers, 2016, 2: 16041. DOI: 10.1038/nrdp.2016.41.
[23]	BAJAJ JS, REDDY KR, O'LEARY JG, et al. Serum levels of metabolites produced by intestinal microbes and lipid moieties independently associated with acute-on-chronic liver failure and death in patients with cirrhosis[J]. Gastroenterology, 2020, 159(5): 1715-1730. e12. DOI: 10.1053/j.gastro.2020.07.019.
[24]	TREBICKA J, BORK P, KRAG A, et al. Utilizing the gut microbiome in decompensated cirrhosis and acute-on-chronic liver failure[J]. Nat Rev Gastroenterol Hepatol, 2021, 18(3): 167-180. DOI: 10.1038/s41575-020-00376-3.
[25]	LIU HX, KEANE R, SHENG L, et al. Implications of microbiota and bile acid in liver injury and regeneration[J]. J Hepatol, 2015, 63(6): 1502-1510. DOI: 10.1016/j.jhep.2015.08.001.
[26]	LIU HX, HU Y, FRENCH SW, et al. Forced expression of fibroblast growth factor 21 reverses the sustained impairment of liver regeneration in hPPARα(PAC) mice due to dysregulated bile acid synthesis[J]. Oncotarget, 2015, 6(12): 9686-9700. DOI: 10.18632/oncotarget.3531.
[27]	FELIPO V, URIOS A, MONTESINOS E, et al. Contribution of hyperammonemia and inflammatory factors to cognitive impairment in minimal hepatic encephalopathy[J]. Metab Brain Dis, 2012, 27(1): 51-58. DOI: 10.1007/s11011-011-9269-3.
[28]	LI HY, DONG LY, YANG JY. Changes of intestinal flora in mice with acute liver[J]. J Pract Med, 2005, 21(19): 2128-2129. DOI: 10.3969/j.issn.1006-5725.2005.19.009. 李海燕, 董礼阳, 杨景云. 急性肝衰竭小鼠肠道菌群变化的研究[J]. 实用医学杂志, 2005, 21(19): 2128-2129. DOI: 10.3969/j.issn.1006-5725.2005.19.009.
[29]	BAJAJ JS, RIDLON JM, HYLEMON PB, et al. Linkage of gut microbiome with cognition in hepatic encephalopathy[J]. Am J Physiol Gastrointest Liver Physiol, 2012, 302(1): G168-G175. DOI: 10.1152/ajpgi.00190.2011.
[30]	CORNELL RP. Restriction of gut-derived endotoxin impairs DNA synthesis for liver regeneration[J]. Am J Physiol, 1985, 249(5 Pt 2): R563-R569. DOI: 10.1152/ajpregu.1985.249.5.R563.
[31]	CORNELL RP, LILJEQUIST BL, BARTIZAL KF. Depressed liver regeneration after partial hepatectomy of germ-free, athymic and lipopolysaccharide-resistant mice[J]. Hepatology, 1990, 11(6): 916-922. DOI: 10.1002/hep.1840110603.
[32]	WANG YS, JI YL, WANG T, et al. Effects of HO-1 on lipopolysaccharide-induced endoplasmic reticulum stress of rat hepatocytes[J]. J Forens Med, 2015, 31(6): 417-421. DOI: 10.3969/j.issn.1004-5619.2015.06.001. 王艳莎, 季英磊, 王涛, 等. HO-1对脂多糖诱导大鼠肝细胞内质网应激的作用[J]. 法医学杂志, 2015, 31(6): 417-421. DOI: 10.3969/j.issn.1004-5619.2015.06.001.
[33]	ZHANG ZH, LI JS, SHI XL. Effects of HO-1 on the expression of HMGB1 and inflammatory cytokines in rats with acute liver failure[J]. J Southeast Univ(Med Sci Edit), 2016, 35(2): 171-175. DOI: 10.3969/j.issn.1671-6264.2016.02.002. 张志恒, 李俊生, 施晓雷. 血红素加氧酶-1对急性肝衰竭大鼠肝组织HMGB1及炎症的影响[J]. 东南大学学报(医学版), 2016, 35(2): 171-175. DOI: 10.3969/j.issn.1671-6264.2016.02.002.
[34]	GU DN, CHEN YP, LU MQ, et al. Role of CD163/HO-1 pathway in a rat acute liver failure model[J]. Chin J Hepatol, 2008, 16(12): 944-945. DOI: 10.3321/j.issn:1007-3418.2008.12.017. 谷甸娜, 陈永平, 卢明芹, 等. CD163和血红素加氧酶1在急性肝衰竭大鼠模型中的表达[J]. 中华肝脏病杂志, 2008, 16(12): 944-945. DOI: 10.3321/j.issn:1007-3418.2008.12.017.
[35]	LYU XY, LI L. Clinical effect of rifaximin in treatment of complications associated with liver cirrhosis[J]. J Clin Hepatol, 2018, 34(7): 1551-1554. DOI: 10.3969/j.issn.1001-5256.2018.07.040. 吕新月, 李磊. 利福昔明在肝硬化相关并发症中的应用[J]. 临床肝胆病杂志, 2018, 34(7): 1551-1554. DOI: 10.3969/j.issn.1001-5256.2018.07.040.
[36]	ALDRIDGE DR, TRANAH EJ, SHAWCROSS DL. Pathogenesis of hepatic encephalopathy: Role of ammonia and systemic inflammation[J]. J Clin Exp Hepatol, 2015, 5(Suppl 1): S7-S20. DOI: 10.1016/j.jceh.2014.06.004.
[37]	AGUSTI A, HERNÁNDEZ-RABAZA V, BALZANO T, et al. Sildenafil reduces neuroinflammation in cerebellum, restores GABAergic tone, and improves motor in-coordination in rats with hepatic encephalopathy[J]. CNS Neurosci Ther, 2017, 23(5): 386-394. DOI: 10.1111/cns.12688.
[38]	European Association for the Study of the Liver. EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis[J]. J Hepatol, 2018, 69(2): 406-460. DOI: 10.1016/j.jhep.2018.03.024.
[39]	SOLÉ C, GUILLY S, DA SILVA K, et al. Alterations in gut microbiome in cirrhosis as assessed by quantitative metagenomics: Relationship with acute-on-chronic liver failure and prognosis[J]. Gastroenterology, 2021, 160(1): 206-218. e13. DOI: 10.1053/j.gastro.2020.08.054.
[40]	WIEST R, ALBILLOS A, TRAUNER M, et al. Targeting the gut-liver axis in liver disease[J]. J Hepatol, 2017, 67(5): 1084-1103. DOI: 10.1016/j.jhep.2017.05.007.
[41]	MORRISETTE T, KEBRIAEI R, LEV KL, et al. Bacteriophage therapeutics: A primer for clinicians on phage-antibiotic combinations[J]. Pharmacotherapy, 2020, 40(2): 153-168. DOI: 10.1002/phar.2358.
[42]	TRANAH TH, EDWARDS LA, SCHNABL B, et al. Targeting the gut-liver-immune axis to treat cirrhosis[J]. Gut, 2021, 70(5): 982-994. DOI: 10.1136/gutjnl-2020-320786.
[43]	DHIMAN RK, RANA B, AGRAWAL S, et al. Probiotic VSL#3 reduces liver disease severity and hospitalization in patients with cirrhosis: A randomized, controlled trial[J]. Gastroenterology, 2014, 147(6): 1327-1337. e3. DOI: 10.1053/j.gastro.2014.08.031.
[44]	GAO J, LI Y, WAN Y, et al. A novel postbiotic from lactobacillus rhamnosus GG with a beneficial effect on intestinal barrier function[J]. Front Microbiol, 2019, 10: 477. DOI: 10.3389/fmicb.2019.00477.
[45]	TAN SZ, XIE BH, CHANG JB, et al. Short-term effect of herbal decoction high position retained enema combined with western drug treatment on patients with damp-heat jaundice of chronic hepatitis B related acute liver failure[J]. J Tradit Chin Med, 2011, 52(13): 1119-1121. DOI: 10.1007/s10570-010-9464-0. 谭善忠, 谢碧红, 常家宝, 等. 中药高位保留灌肠联合西药治疗慢性乙型肝炎肝功能衰竭湿热发黄证患者近期疗效[J]. 中医杂志2011, 52(13): 1119-1121. DOI: 10.1007/s10570-010-9464-0.
[46]	SORRIBAS M, JAKOB MO, YILMAZ B, et al. FXR modulates the gut-vascular barrier by regulating the entry sites for bacterial translocation in experimental cirrhosis[J]. J Hepatol, 2019, 71(6): 1126-1140. DOI: 10.1016/j.jhep.2019.06.017.
[47]	BAJAJ JS, SALZMAN NH, ACHARYA C, et al. Fecal microbial transplant capsules are safe in hepatic encephalopathy: A phase 1, randomized, placebo-controlled trial[J]. Hepatology, 2019, 70(5): 1690-1703. DOI: 10.1002/hep.30690.
[48]	BAJAJ JS, KASSAM Z, FAGAN A, et al. Fecal microbiota transplant from a rational stool donor improves hepatic encephalopathy: A randomized clinical trial[J]. Hepatology, 2017, 66(6): 1727-1738. DOI: 10.1002/hep.29306.
[49]	YANG JM, SUN Y, WANG M, et al. Regulatory effect of a Chinese herbal medicine formula on non-alcoholic fatty liver disease[J]. World J Gastroenterol, 2019, 25(34): 5105-5119. DOI: 10.3748/wjg.v25.i34.5105.
[50]	POSE E, TREBICKA J, MOOKERJEE RP, et al. Statins: Old drugs as new therapy for liver diseases?[J]. J Hepatol, 2019, 70(1): 194-202. DOI: 10.1016/j.jhep.2018.07.019.
[51]	ALBILLOS A, de GOTTARDI A, RESCIGNO M. The gut-liver axis in liver disease: Pathophysiological basis for therapy[J]. J Hepatol, 2020, 72(3): 558-577. DOI: 10.1016/j.jhep.2019.10.003.